Process for producing certain intermediates for 1,4-benzodiazepines



United States Patent US. Cl. 260-2943 6 Claims ABSTRACT OF THEDISCLOSURE 1,4-benzothiazepines (A) bearing aromatic or alkylsubstituents in the -position are prepared by first reacting a diazoniumcompound with a copper thiocyanate. The diazonium compound is hydrolyzedto the corresponding Z-mercapto compound which in turn is reacted withan amino-lower alkyl halide to give the correspondingZ-aminoethylthiophenyl ketone. The latter is ring closed to (A) above.(A) is useful as muscle relaxants and anticonvulsants.

RELATED APPLICATIONS This application is a division of Ser. No. 417,855,filed Dec. 14, 1964, now Pat. No. 3,362,962, dated Jan. 9, 1968, whichin turn is a continuatiou-in-part of Ser. No. 339,910, filed Jan. 24,1964 (now abandoned), both filed in the names of Earl Reeder and LeoHenryk Sternbach. The benefit of the filing dates of these earlierapplications is hereby claimed.

BRIEF SUMMARY This invention relates to novel compounds having aheterocyclic ring structure containing nitrogen and sulfur as the heteroatoms, to methods for producing such com pounds, to novel derivatives ofsuch compounds and to novel intermediates useful in the preparation ofsaid heterocyclic ring compounds. More particularly, the inventionrelates to novel 1,4-benzothiazepines, to a method for producing suchcompounds, to novel derivatives of such 1,4-benzothiazepines and tonovel intermediates useful in the preparation of 1,4-benzothiazepines.

DETAILED DESCRIPTION The compounds of this invention can be representedby the following structural formulae 3,530,139 Patented Sept. 22, 1970 Mice wherein D is selected from the group consisting of and lower alkyl,

I X is selected from the group consisting of sulfonyl; Z is selectedfrom the group consisting of thio, sulfinyl and sulfonyl; R and R areselected from the group consisting of hydrogen, halogen, nitro, loweralkyl, lower alkoxy, trifluoromethyl, lower alkyl thio, lower alkylsulfinyl and lower alkyl sulfonyl; R is selected from the groupconsisting of hydrogen, lower alkyl, halogen and trifluoromethyl; R andR are selected from the group consisting of hydrogen and lower alkyl;and R is selected from the group consisting of hydrogen,

lower alkyl where m is a whole integer from 2-7 and R is selected fromthe group consisting of hydrogen and lower alkyl, lower acyl, loweralkenyl and lower alkynyl. Preferably, R is positioned on thebenzothiazepine nucleus at the 7-position and R is hydrogen. Still morepreferably, R is positioned on the benzothiazepine nucleus at the7-position and R is hydrogen and if D includes a phenyl radical, R ispositioned on the phenyl radical at the 2-position thereof.

The expression lower alkyl, as utilized through the instantspecification, is intended to connote both straight and branched chainhydrocarbon groups such as methyl, ethyl, propyl and isopropyl. The termhalogen, as used throughout the disclosure, is intended to connote allfour halogens, namely, chlorine, bromine, iodine and fluorine. Preferredamong the halogens for the purpose of the present invention are bromineand chlorine. Lower alkyl thio, as used throughout the disclosure,represents a group such as methyl-thio and the like. The expressionslower alkenyl and lower alkynyl represent straight or branched chainmonoethylenically unsaturated hydrocarbon groups and acetylenichydrocarbon groups such as allyl and propargyl. The expression loweralkoxy connotes a group such as, preferably, methoxy and ethoxy and thelike. Each R can represent the same or different groups. Preferably,they are the same and hydrogen. R is similarly preferably hydrogen.

Compounds corresponding to Formulae I, In, 1/), Ic and Id above formacid addition salts with pharmaceutically acceptable inorganic ororganic acids. Among the acids suitable for the salt-forming purpose areincluded such acids as mineral acids, e.g., hydrohalic acids such ashydrochloric acid, hydrobromic acid and the like, nitric acid, sulfonicacid, phosphorus acid, etc. and organic acids such as methane-sulfonicacid, succinic acid, citric acid, tartaric acid, maleic acid and thelike.

One process aspect of the invention relates to the preparation ofcompounds corresponding to Formula Ib above wherein Z is thio, i.e.,compounds having the formula R she-Rt R1 I CH-R4 wherein D, R, R R and Rare as above. Such a preparation involves initially reacting thecorresponding 2- aminobenzene ketone with nitrous acid in the presenceof an excess of a strong mineral acid, e.g., hydrochloric acid, sulfuricacid and the like. The resulting mixture may be treated with a salt of afluoroboric acid such as an alkali metal salt, e.g., sodiumfluoroborate. In this manner diazonium compounds are prepared having theformula D III wherein D, R and R are as above and X is selected from thegroup consisting of an anion of a strong mineral acid and the radical BFll S C lower alkyl wherein R, R and D are as above which can then behydrolyzed, preferably under basic conditions, employing conventionalhydrolysis techniques to compounds having the formula wherein R, R and Dare as above.

4 Suitable xanthates have the formula it YSC 0 lower alkyl wherein Y isan alkaline earth metal or an alkali metal.

Compounds of Formula V can also be prepared from compounds of FormulaIII above by treating compounds of Formula III above with a metalthiocyanate, e.g., copper thiocyanate, to give a compound having theformula of IESCN O O wherein R, R and D are as above,

and thereafter hydrolyzing, preferably under basic conditions, theresulting compound of Formula VI to compounds of the Formula V aboveutilizing conventional hydrolyzing techniques.

According to the present invention, compounds of Formula V are thenreacted with or without isolation with a compound of the formula Ira R415 VII wherein D, R, R R and R have the same meaning as ascribed theretohereinabove.

Compounds of Formula VII can be further reacted with or withoutisolation from the reaction medium in which they are prepared to producecompounds having the Formula II above. For example, the reaction mixturecontaining the compounds of Formula II above and Formula VII abovewithout isolating either can be heated in the presence of an inertorganic solvent such as pyridine and the like whereby to eifectcyclization of compounds Corresponding to Formula VII above. Thus, theyield of compounds corresponding to Formula II above is increased.

Compounds of Formula VII above can also be prepared by reacting acompound of the formula halo wherein R, R and D are as above with acompound of the formula R R4 HS(II(IJHNHZ in the presence of a strongbase, preferably an alkali metal hydroxide or an alkali metal alkylateor an alkali metal hydride, e.g., sodium hydride and an inert organicsolvent such as pyridine. The soformed compounds of Formula VII abovecan then be heated in the presence of an inert organic solvent such aspyridine and the like whereby ring closure to compounds of Formula IIabove occurs.

The so-cyclized compounds of Formula II above are then either (1)preferably treated with a peracid or hydrogen peroxide whereby to yieldcompounds of Formula Ic above or (2) treated with lithium aluminumhydride whereby to yield compounds of Formula Ia above wherein Z is thioand R is hydrogen or (3) treated with preferably a periodate, e.g.,sodium periodate or carefully treated with a calculated amount of otherperacids whereby to yield a compound of the formula Ib above wherein Zis sulfinyl.

In one procedure, a compound of Formula II above is treated with anyconvenient peracid such as peracetic acid or hydrogen peroxide at atemperature of 0150, preferably -60 in the presence of an acid such asacetic acid and the like whereby to prepare an epoxide of formula 10above, i.e., a compound of the formula wherein X, D, R, R R and R havethe same meanings as ascribed thereto hereina'bove.

The resulting compound when heated in the presence of an inert organicsolvent such as xylene, toluene and the like gives compounds of theFormula I above having the formula of D 0 IX wherein X, D, R, R R and Rhave the same means as above.

Compounds of Formula IX can be deoxygenated in the 4-position bytreatment with a reducing agent such as phosphorus trichloride or byhydrogenating in the presence of Raney nickel. The resultant compoundwhich has the Formula Ib above wherein Z is sulfonyl can be furtherreduced by hydrogenation in the presence of a conventional hydrogenationcatalyst such as a noble metal, e.g., platinum oxide and the like or analkali metal or an alkaline earth metal borohydride such as sodiumborohydride whereby to provide compounds having the Formula Ia abovewherein Z is sulfonyl, 2,3,4,5-tetrahydro-1,4-benzodiazepine1,1-dioxides.

Compounds of Formula II above can also be treated with an oxidant suchas a periodate, e.g., an alkali metal periodate, to provide thecorresponding compound wherein Z is sulfinyl.

In yet another procedure, the product resulting from the performance ofthe final stage of the processes described in connection with thepreparation of compounds of Formula II above (e.g., compoundscorresponding to Formula II above) can be reduced with lithium aluminumhydride as is noted above or by catalytic hydrogenation in the presenceof a noble metal such as platinum whereby to provide compounds havingthe formula /Rn R so m R1 OH-Rl OH-NH XI wherein D, R, R R and R are asabove.

Compounds of Formula XI can be further selectively treated with either ametal periodate to yield the corresponding compounds having a sulfinylgroup in the 1- position or with a strong oxidizing agent, e.g., aperacid such as peracetic acid or trifluoroperacetic acid or hydrogenperoxide, to provide the corresponding compounds having a sulfonyl groupin the 1-position.

The treatment with lithium aluminum hydride as described above, i.e.,the formation of 2,3,4,5-tetrahydro- 1,4-benzothiazepines, in everyinstance is effected at a temperature of -20 to preferably 5 to +40 C.,in the presence of any conveniently available inert organic solvent suchas tetrahydrofuran or an'ether such as diethyl ether, dimethyl ether andthe like. The treatment with an alkali metal periodate as describedabove, i.e., the formation of 1,4-benzothiazepine l-oxides in everyinstance is effected preferably in the presence of an inert organicsolvent such as an alcohol, e.g., methanol, ethanol and the like, aketone such as acetone and methyl ethyl ketone, dioxane and the like ata temperature in the range of 10 to +60, preferably -5 to +40. Suchtreatment leads to compounds of the formulae set out above wherein Z issulfinyl. The same effect may be achieved by the use of calculatedamounts of a peracid such as peracetic acid or trifluoro peracetic acid.

In an alternate procedure for the preparation of compounds correspondingto Formula VII above (compounds which on heating in the presence of aninert organic solvent such as pyridine and the like cyclize to compoundsof the Formula II above), a compound corresponding to Formula V above,preferably, one wherein R is nitro and R is hydrogen is reacted with acompound having the formula of Essentially, all that is required of thegroups represented by R and R when other than hydrogen, is that they bereadily hydrolyzable utilizing conventional techniques.

The resulting compound which has the formula wherein D, R, R R R R and Rare as above X III can be hydrolyzed to compounds having the Formula VIIunder acid conditions, for example.

Compounds of Formula XIII above wherein R is nitro and R is hydrogen canby hydrogenated in the presence of any suitable reducing system such asone which includes iron to yield the corresponding compound wherein R isamino. The resultant amino derivative thereafter, if desired, can beconverted into the corresponding compound wherein R is halogen by thetreatment thereof with nitrous acid in the presence of a strong mineralacid, e.g., hydrochloric acid, followed by treatment of the resultingsubstance with a strong hydrohalic acid, e.g., hydrochloric acid, in thepresence of a copper catalyst, e.g., cuprous chloride, cuprous bromideand the like. The

resulting compound wherein R is halogen is hydrolyzed employing acidhydrolysis techniques, e.g., in the presence of acetic acid and ahydrohalic acid, to yield a compound having the Formula VII abovewherein R is halogen. The last-mentioned compounds, as is noted above,can be cyclized employing the techniques recited hereinabove andexemplified hereinafter. Compounds of Formula VIII are useful asappetite suppressants as well as intermediates in the preparation ofcompounds of Formula H above.

Compounds corresponding to Formula Ia above wherein R is lower alkyl,lower alkenyl and lower alkynyl can be synthesized from thecorresponding compounds corresponding to Formula In above wherein R ishydrogen by alkylating or alkenylating or alkynylating such compounds.The alkylation can proceed, for example, by forming the sodio derivativeof compounds corresponding to Formula I above wherein R is hydrogen witha sodium alkylate such as sodium methoxide in an inert organic solventsuch as toluene and then reacting the sodio derivate with, for example,dialkyl sulfate or an alkyl halide in an inert solvent, for example, ahydrocarbon or dimethylformamide. Suitable dialkyl sulfates may berepresented by dimethyl sulfate. Similarly, suitable alkyl halides maybe represented by methyl iodide. Analogously, the alkenylation can beeffected using an alkenyl halide, e.g., allyl bromide and thealkynylation can be effected using an alkynyl halide, e.g., propargylbromide. Alternatively, the positioning of the alkyl or the alkenyl orthe alkynyl group thusly can be effected under analogous reactionconditions without first forming the said sodio derivative.

Compounds of the Formula In above wherein R is a lower group can besynthesized from the corresponding compounds of Formula Ia above whereinR is hydrogen by reacting the said last-mentioned compounds with acompound of the formula wherein m is a whole integer from 2 to 7, R isselected from the group consisting of hydrogen and lower alkyl and X isa halogen atom selected from the group consisting of chlorine, bromineand iodine.

The above reaction can be conducted in an inert solvent medium utilizingone or more inert organic solvents such as methanol, ethanol,chlorobenzene, benzene, dimethylformamide, toluene or the like.Temperature and pressure are not critical and the positioning of a basicside chain on compounds corresponding to Formula Ia above at R thereofcan be carried out at room temperature and atmospheric pressure and atelevated temperatures and/or elevated pressures.

Compounds of Formula Id above can be prepared by treating compounds ofFormula I above wherein one of the R groups is hydrogen with, forexample, an anhydride of a lower alkanoic acid, e.g., acetic anhydride.Compounds of Formula Id above can be further carefully treated withlithium aluminum hydride to thereby prepare the corresponding compoundof Formula Ib above wherein one of the IR groups is hydrogen.

Compounds of Formula Ib above wherein one of the R groups is hydrogencan be treated with a halogenating agent, e.g., thionyl halide such asthionyl chloride or sulfuryl chloride to thereby provide thecorresponding compound wherein Z is thio and which has halogen 8 thereonin position-2. Accordingly, there are obtained compounds of the formulahalo wherein R, R R R and D are as above.

Compounds of Formula Ib above wherein Z is thio or sulfinyl can betreated with an acid, e.g., a hydrohalic acid, such as hydrochloric orhydrobromic acid and the like to obtain compounds of Formula VII aboveand compounds having the formula XIV wherein R, R R R and D are asabove. The lastmentioned compounds are useful as anticonvulsants.

A preferred class of compounds included within the purview of thepresent invention are compounds of the formula XVI wherein R, R R R andR are as above.

i lower alkyl wherein R, R R and R are as above.

Still another preferred class of compounds within the purview of thepresent invention are compounds of the formula XIX wherein R, R R and Rare as above.

In this aspect of the present invention, the S-pyridyl moiety ispreferably joined to the benzothiazepine nucleus at the 2-position ofthe S-pyridyl ring.

The substituent designated R in compounds of the formulae above can beobtained as other than hydrogen by treatment of the starting materialsor by treatment of the end product 1,4-benzothiazepines. For example,the said end products wherein R is nitro and R is hydrogen, can beobtained by treating the 1,4-benzothiazepine end products wherein R andR are both hydrogen with nitric acid in the presence of sulfuric acid inthe manner well known per se.

Compounds of Formulae XIV through XIX form medicinally acceptable acidaddition salts with pharmaceutically acceptable acids including bothinorganic and organic acids such as hydrochloric acid, hydrobromic acid,nitric acid, sulfuric acid, acetic acid, formic acid, succinic acid,maleic acid, p-toluene sulfonic acid, and the like.

Compounds corresponding to Formulas I, Ia, Ib, Ic, Id and, of course,Formulas XIVXIX above are useful as muscle relaxants andanticonvulsants. They can be administered internally, for exampleparenterally or enterally in conventional pharmaceutical dosage formswith dosage adjusted to individual needs. For example, they can beadministered in conventional liquid or solid vehicles to provideelixers, suspensions, tablets, capsules, powders and the like, accordingto acceptable pharmaceutical practices.

The following examples are illustrative but not limitative of theinvention. All temperatures designated through out the disclosure are indegrees Centigrade, unless otherwise state.

EXAMPLE 1 To 450 ml. of concentrated sulfuric acid, cooled to 76 g. (1mole) of sodium nitrite was added slowly with stirring. The mixture wasthen heated to about 80 until a clear solution formed. After cooling to30, 232 g. (1 mole) of 2-amino-S-chlorobenzophenone was added inportions keeping the temperature between 30 402 After stirring for 1hour, the solution was poured slowly into 3 l. of ice-water. Afterfiltration, a solution of 200 g. of sodium fluoroborate in 800 ml. ofwater was added. 2-Benzoyl-4-chloro-benzenediazonium fluoroborateprecipitated. The product was separated by filtration and washed with asmall amount of water.

EXAMPLE 2 The fluoroborate of Example 1 was added within 5 minutes to avigorously stirred solution of 240 g. (1.5 mole) of potassium ethylxanthate in 1.5 l. of water heated to 75. After the addition wascompleted, the mixture was stirred for minutes, cooled and extractedwith ether. The ether extract was dried over sodium sulfate, filteredand the filtrate concentrated in vacuo to dryness yielding the ethylXanthic acid 2-benzoyl-4-chlorophenyl ester as the residue.

EXAMPLE 3 The residue of Example 2 was added to a solution of 240 g. ofpotassium hydroxide in a mixture of 600 ml. of water and 600 ml. ofethanol. The reaction mixture was stirred and refluxed for 15 minutes,while 35 g. of zinc dust was carefully introduced. One liter of waterwas then added and the mixture filtered over a filter aid, and washedwith 500 ml. of water. The filtrate containing the thiophenol,5-chloro-2-mercapto benzophenone, was cooled to room temperature and asolution of 204 g. of bromoethylamine hydrobromide in 350 ml. of waterwas added. After stirring for 15 minutes, the reaction mixture wasextracted with methylene chloride and the organic layer dried oversodium sulfate and fil tered. The filtrate was acidified with methanolichydrochloric acid and concentrated in vacuo. To the residue consistingof 7-chloro'2,3-dihydro-5-phenyl-1,4-benzothiazepine and5-chloro-2-(2-aminoethylthio)benzophenone, 1 liter of pyridine wasadded. The solution was refluxed for 1 hour, then concentrated in vacuoand the residue dissolved in a mixture of methylene chloride and water.The organic layer was separated, dried, filtered and the filtrateacidified with ethanolic hydrochloric acid and diluted with about 300ml. of ethanol. The solution was concentrated in vacuo to removemethylene chloride. 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepinehydrochloride, melting at about 230, was separated by filtration andwashed with a small amount of ethanol. Recrystallization from a mixtureof ethanol and ether gave yellow prisms of the product melting at233-234" (dec.).

EXAMPLE 4 A solution of 125 g. of copper sulfate in 500 ml. of water wascombined with a solution of g. of sodium thiocyanate in 25 0 ml. ofwater. The precipitated copper thiocyanate was separated by filtration,washed with water and was suspended in 500 ml. of water. To this mixturewas added 50 g. of sodium thiocyanate and2-benzoyl-4-chloro-benzenediazonium fluoroborate prepared from /2 moleof the aminobenzophenone as in Example 1. The mixture was stirred for 24hours at room temperature. The solids containing the reaction productwere separated by filtration, washed with cold water and extracted withboiling alcohol (about 1 liter). The hot alcohol solution was filteredto remove the copper thiocyanate. On cooling,5-chloro-2-thiocyanobenzophenone crystallized from the alcohol solution.The product was purified by recrystallization from ethanol and formedcream-colored needles melting at 98-99.

EXAMPLE 5 A mixture of 78 g. of 5-chloro-2-thiocyanobenzophenone in 800ml. of alcohol, 200 ml. of 40 percent sodium hydroxide and 60 g. ofsodium hydrosulfite was refluxed for /2 hour.2-mercapto-S-chlorobenzophenone formed and was then alkylated withbromoethylamine hydrobromide as described in Example 3. Furthertreatment with pyridine as described in Example 3 gave 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine hydrochloride which, afterrecrystallization, was found to have a melting point of 233234 (dec.).

The free base was liberated from the above hydrochloride with sodiumhydroxide and extracted with ether. The ether solution was concentratedin vacuo and 7- chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepinecrystallized from ether as colorless prisms melting at 79-80.

EXAMPLE 6 A solution of 34 g. (0.125 mole) of7-chloro-2,3-dihydro-S-phenyl-l,4-benzothiazepine hydrochloride in 200ml. of dry tetrahydrofuran was carefully added at room temperature to astirred suspension of 10 g. (0.25 mole) of lithium aluminum hydride in600 ml. of tetrahydrofuran. The reaction mixture was refluxed for 2hours then cooled in an ice-bath. One liter of wet ether was addedslowly and the mixture filtered through a hyflo bed. The filtrate wasdried, concentrated in vacuo to dryness and the residue dissolved inethanol. The solution was acidified with an excess of methanolichydrogen chloride. On addition of ether, 7-chloro-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine hydrochloride was obtained.

Recrystallization of the product from a mixture of ethanol and ethergave slightly yellow needles melting at 267268.

EXAMPLE 7 To a stirred solution of 5.4 g. (0.02 mole) of 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine hydrochloride in 200 ml. ofmethanol cooled in an ice-bath, 4.5 g. (0.021 mole) of sodiummeta-periodate dissolved in 42 ml. of water was added. The reactionmixture was stirred for 6 hours with ice cooling and 14 hours at roomtemperature. The precipitated sodium iodate was separated by filtrationand the filtrate concentrated in vacuo to a small volume. Theconcentrate was extracted with methylene chloride and the organic layerwas separated, dried and concentrated in vacuo to dryness. The residuethus obtained was dissolved in methanol and acidified with methanolichydrogen chloride. Addition of ether gave7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine l-oxide hydrochloride.Recrystallization of the product from a mixture of methanol and ethergave slightly yellow prisms melting at 206207.

EXAMPLE 8 To a stirred solution of 4 g. (0.014 mole) of 7-chloro-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine hydrochloride in 100 ml.of methanol cooled in an ice bath, 3.2 g. (0.015 mole) of sodiummeta-periodate dissolved in 28 ml. of water was added. The reactionmixture was stirred for 5 hours with ice cooling and 23 hours at roomtemperature. The precipitated sodium iodate was separated by filtrationand the filtrate concentrated in vacuo to a small volume. Theconcentrate was extracted with methylene chloride and the organic layerwas separated, dried and concentrated in vacuo to dryness. A methanolsolution of the residue was acidified with methanolic hydrogen chloride.On addition of ether 7-chloro-2,3,4,5-tetrahydro-S-phenyl-1,4-benzothiazepine 1 oxide hydrochloridecrystallized. Recrystallization from a mixture of methanol and ethergave colorless prisms of the product melting at 230-231".

The base was liberated from the hydrochloride with alkali andcrystallized from ether as colorless prisms melting at 116117.

EXAMPLE 9 A solution of 43.2 g. (0.158 mole) of7-chloro-2,3-dihydro-S-phenyl-1,4-benzothiazepine hydrochloride in 400ml. of acetic acid and 70 ml. of 30 percent hydrogen peroxide was leftat room temperature exposed to daylight for 14 days.7-chloro-4,5-epoxy-2,3,4,5-tetrahydro- S-phenyl-1,4-benzothiazepine1,1-dioxide precipitated and was separated by filtration. Onrecrystallization from methylene chloride, colorless prisms of theproduct were obtained which, when introduced into a melting pointapparatus at 220, melted at 205 then resolidified and remelted at265-266.

EXAMPLE 10 A mixture of 5 g. of7-chloro-4,5-epoxy-2,3,4,5-tetrahydro-S-phenyl-1,4-benzothiazepine1,1-dioxide in 100 ml. of boiling Xylene was refluxed for 10 minutes andthen cooled. 7-chloro-2,3-dihydro 5 phenyl-1,4-benzothiazepine1,1,4-trioxide formed and was separated by filtration. The product wascrystallized from methylene chloride as colorless needles melting at265266.

EXAMPLE 1 1 To a stirred suspension of 7.3 g. (0.022 mole) of 7-chloro-2,3-dihydro-5-phenyl 1,4 benzothiazepine-1,1,4- trioxide in 300ml. of chloroform, 9 ml. (0.1 mole) of phosphorous trichloride wasadded. The reaction mixture was refluxed for 1 hour then cooled and icedand an excess of 50 percent potassium hydroxide added. The mixture wasstirred at room temperature until complete solution was achieved. Theorganic layer was separated, dried and concentrated in vacuo to dryness.The residue crystallized from acetone and yielded7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine 1,1-dioxide.Recrystallization from acetone gave colorless prisms of the productmelting at 164-165".

EXAMPLE 12 A solution of 21.3 g. (0.07 mole) of7-chloro-2,3-dihydro-5-phenyl-1,4benzothiazepine 1,1-dioxide in 200 ml.of acetic acid and ml. of water was hydrogenated at room temperature andatmospheric pressure in the presence of 1.8 g. of platinum oxide. Afterthe absorption of 1.2 liter of hydrogen (21 hours) the catalyst wasseparated by filtration and the filtrate concentrated in vacuo todryness. The residue was dissolved in methylene chloride, washed withdilute alkali and the organic layer dried and concentrated to a smallervolume. The concentrate (ca. 50 ml.) was adsorbed on a column preparedwith 200 g. of Woelm grade I alumina. On elution of the column withmethylene chloride, the first 250 m1. of eluate (after concentration todryness in vacuo), gave a residue which crystallized from ether to yield7-chloro-2,3,4,5- tetrahydro-S-phenyl-l,4-benzothiazepine 1,1-dioxide.Recrystallization from ether gave colorless plates of the productmelting at 159160.5.

EXAMPLE 13 A stirred suspension of 19.2 g. (0.06 mole) of 7-ch1oro-2,3-dihydro-5-phenyl 1,4 benzothiazepine-1,1,4- trioxide in 200ml. of acetic anhydride was refluxed for 5 hours. After concentration ofthe reaction mixture in vacuo to dryness, the residue was crystallizedfrom benzene yielding 7-chloro-5-phenyl-1,4-benzothiazepine 1,1-dioxide. The product was recrystallized from a mixture of methylenechloride and ether as yellow prisms having a melting point of 207208.

EXAMPLE 14 To a suspension of 0.8 g. (0.021 mole) of lithium aluminumhydride in 90 ml. of dry tetrahydrofuran, 1.5 g. (0.005 mole) of7-chloro-5-phenyl-1,4-benzothiazepine 1,1-dioxide was added. Thereaction mixture was stirred at room temperature for 30 minutes thencooled in an ice-bath and the excess of lithium aluminum hydride wasdestroyed by the gradual addition of wet ether. The reaction mixture wasfiltered through hyfio and the filtrate was dried and concentrated invacuo to dryness. The residue was dissolved in ethanolic hydrogenchloride and the hydrochloride precipitated by the addition of acetone.The crude salt was separated and converted into7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine 1, l-dioxide bytreatment with alkali and crystallization from acetone.Recrystallization from acetone gave colorless prisms of the productmelting at 164165.

EXAMPLE 15 A solution of 5.8 g. (0.02 mole) of7-chloro-2,3-dihydro-S-phenyl-l,4-benzothiazepine l-oxide hydrochloridein ml. of 3 N hydrochloride acid was heated for 4 hours on a steam bath.The reaction mixture was concentrated in vacuo to dryness.Crystallization of the residue from a mixture of ethanol and isopropanolyielded 5 chloro-2-(Z-aminoethylsulfinyl)benzophenone melting about 150.Light yellow needles of the product melting at 152153 crystallized froma mixture of methanol and ether.

The above hydrochloride was converted to the ring closed startingmaterial in boiling pyridine.

EXAMPLE 16 To ml. of thionyl chloride, 18.5 (0.065 mole) of7-chloro-2,3-dihydro-5-phenyl 1,4 benzothiazepine 1- oxide hydrochloridewas carefully added. When the reaction had subsided, the reactionmixture was poured onto ice, made alkaline with 50 percent potassiumhydroxide and extracted with methylene chloride. The organic layer wasseparated, dried and concentrated in vacuo to dryness. The residue wascrystallized from a mixture of ether and petroleum ether yielding2,7-dichloro-2,3-dihydro-5- phenyl-1,4-benzothiazepine.Recrystallization from ether yielded colorless prisms of the productmelting at 133 134.

EXAMPLE 17 To a stirred solution of 6.8 g. (0. 06 mole) of2-mercaptoethylamine hydrochloride in ml. of dimethvl- 13 formamide, 6.6g. (0.122 mole) of sodium methoxide was added. The mixture was heated at40-50 for 15 minutes, 15.6 g. (0.06 mole) of2-chloro-5-nitrobenzophenone was then added and stirring was continuedfor 3 hours at room temperature. Dilute sodium hydroxide was added andthe product was extracted with methylene chloride. The organic layer wasseparated, dried and concentrated in vacuo to a small volume.5-nitro-2-(aminoethyltdio)benzophenone crystallized and was separated byfiltration. Recrystallization from methylene chloride gave the productas yellow needles melting at 189-190".

EXAMPLE 18 A mixture of 10.4 g. (0.04 mole) of 2-mercapto-5-nitrobenzophenone, 800 ml. of methanol, 2.2 g. (0.04 mole) of sodiummethoxide and g. (0.04 mole) of {3- bromoethylphthalimide was refluxedfor 17 hours and then concentrated in vacuo to dryness. The residue wasextracted with methylene chloride and washed with dilute sodiumhydroxide. The organic layer was dried and concentrated in vacuo to asmaller volume. The concentrate was diluted with petroleum ether.N-[2-(2-benzoyl 4 nitrophenylthio)ethyl1phthalirnide precipitated andwas found to have a melting point at 120-123. Recrystallization from amixture of methylene chloride and petroleum ether gave yellow prisms ofthe product melting at 126-127".

EXAMPLE 19 To a stirred suspension of 10 g. (0.023 mole) of N-[2-(2-benzoyl-4-nitrophenylthio)ethyl]phthalimide in a mixture of 100 ml.of acetic acid and 100 ml. of water heated on a stem bath, 7.5 g. ofiron filings (40' mesh) was added carefully over a period of 45 minutes.The reaction mixture was heated an additional 30 minutes, then filteredthrough hyfio. The filtrate was diluted with water and extracted withmethylene chloride. The organic layer was washed with cold dilutepotassium hydroxide, dried and concentrated in vacuo to dryness.Crystallization of the residue from a mixture of ethanol, ether andpetroleum ether yielded N-[2-(4-amino-2 benzoylpheny1-thio)ethy1]phthalimide melting at 107113. Light yellow prisms of theproduct melting at 115116 were obtained on crystallization from ethanol.

EXAMPLE 20 To a cooled suspension of 4 g. (0.01 mole) of N-[2-(4-amino-2-benzoylphenylthi0)ethyl]phthalimide in 60 ml. of 3 Nhydrochloric acid, 11 ml. of 1 N sodium nitrate was added within 10minutes at 0-5. The reaction mixture was stirred at 0-5 for 45 minutesand then added to a solution of 2 g. (0.02 mole) of cuprous chloride in40 ml. of concentrated hydrochloric acid at room temperature. Thereaction mixture was stirred for 2 hours at room temperature then pouredonto ice, made alkaline with an excess of ammonium hydroxide andextracted with methylene chloride. The methylene chloride layer wasdried, concentrated in vacuo to a volume of about 50 ml. and thenfiltered through g. of Woelm grade I alumina. The filter bed was washedwith methylene chloride and the filtrate collected in fractions. Thefirst 50 ml. of filtrate was concentrated in vacuo to dryness and theresidue crystallized from ether to give N- [2 (2benzoyl-4-chlorophenylthio)ethylJphthalimide. Colorless prisms of theproduct melting at 106107 were obtained on recrystallization from ether.

EXAMPLE 21 A solution of 0.8 g. (0.002 mole) of N-[2-(2-benzoyl-4-chlorophenylthio) ethyl] phthalimide in a mixture of ml. of aceticacid and concentrated hydrochloric acid was refluxed for 17 hours. Thereaction mixture was poured onto ice, made alkaline with percentpotassium hydroxide and extracted with methylene chloride.

The organic layer was separated, dried, acidified with hydrogen chlorideand concentrated in vacuo to dryness. The residue crystallized from amixture of ethanol and eher to give5-chloro-2-(2-aminoethylthio)benzophenone hydrochloride.Recrystallization from a mixture of ethanol and ether gave the productas pale yellow needles melting at 168-169". Similarly, N-[2(2benzoyl-4-nitrophenylthio)ethyl]phtalimide can be converted to S-nitro-2 aminoethylthio) benzophenone.

EXAMPLE 22 A solution of 1.9 g. (0.061 mole) of7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine hydrochloride in 20ml. of 3 N hydrochloric acid was heated on the steambath for 1 hour. Theturbid reaction mixture was poured into ice water, made alkaline andextracted with methylene chloride. The organic layer was dried andconcentrated in vacuo to dryness and the residue thus obtained dissolvedin methanol and acidified with methanolic hydrogen chloride. On additionof ether 5-chloro-2-(2-aminoethylthio)benzophenone hydrochloridecrystallized and was found to have a melting point of 160-161.Recrystallization of the product from a mixture of ethanol and ethergave the product as pale yellow needles melting at 168169.

EXAMPLE 23 To 450 ml. of concentrated sulfuric acid, cooled to 10, 69 g.(1 mole) of sodium nitrite was added slowly with stirring. The mixturewas then heated to about 80 until a clear solution formed. After coolingto 30, 197 g. (1 mole) of 2-aminobenzophenone was added in portionskeeping the temperature between 30.40. After stirring for 1 hr., thesolution was poured slowly into 3 liters of ice-water. After filtration,a solution of 200 g. of sodium fiuoroborate in 800 ml. of water wasslowly added to the filtrate with stirring. 2-benzoyl-benzenediazoniumfluoroborate precipitated and was separated by filtration. Theprecipitate was washed with a small amount of water. The so-washedprecipitate was added over a period of 10 minutes to a vigorouslystirred solution of 240 g. (1.5 mole) of recrystallized potassium ethylxanthate 1 in 1.5 liter of water heated to After the addition wascompleted, the mixture was stirred for 5 min., cooled and extracted withether. The ether extract was dried over sodium sulfate, filtered, andthe filtrate concentrated in vacuo to dryness yielding a crudecontaining ethyl xanthic acid 2-benzoylphenyl ester. A solution of 240g. of potassium hydroxide in a mixture of 600 ml. of water and 600 ml.of ethanol was added to the crude. The reaction mixture was then stirredand refluxed for 15 min., while 35 g. of zinc dust was carefullyintroduced. One liter of water was then added, and the mixture wasfiltered over a filter aid, and washed with 500 ml. of water. Thefiltrate containing 2-mercapto benzophenone was cooled to roomtemperature, and a solution of 20 g. of bromoethylamine hydrobromide in350 ml. of water was added. After stirring for 15 min., the reactionmixture was extracted with methylene chloride and the organic layerdried over sodium sulfate and filtered. The filtrate was acidified withmethanolic hydrochloric acid and concentrated in vacuo. To the residuewhich contained 2-(2-aminoethylthio) benzophenone and2,3-dihydro-5-phenyl-1,4-benzothiazepine there was added one liter ofpyridine. The solution was refluxed for 1 hr., then concentrated invacuo and the residue dissolved in a mixture of methylene chloride andwater. The organic layer was separated, dried, and concentrated in vacuoto dryness. The oily residue was dissolved in ether and filtered over500 g. of Woelm grade I alumina. The filter bed was then washed withether. The filtrate was concentrated in vacuo to dryness and the residuewas crystallized from a mixture of ether and petroleum ether. The crudeproduct was purified by re- Technical grade ethyl xanthate wasrecrystallized from a. five-fold amount of boiling ethanol.

crystallization from the same solvent mixture and gave2,3-dihydro-5-phenyl 1,4 benzothiazepine as colorless prisms melting at6465.

A solution of 7 g. of 2,3-dihydro-5-phenyl-1,4-benzothiazepine in anexcess of methanolic hydrogen chloride was concentrated in vacuo todryness. The residue was crystallized twice from a mixture of methylenechloride and ether, and formed yellow prisms of 2,3-dihydro-5-phenyl-1,4-benzothiazepine hydrochloride melting at 201 202.

EXAMPLE 24 A solution of 250 g. of copper sulfate in 1 liter of hotwater was combined with a solution of 223 g. of potassium thiocyanate in500 ml. of water. The precipitated copper thiocyanate was separated byfiltration, washed with water and suspended in 1 liter of water. To thismixture Was added 100 g. of potassium thiocyanate and crude2-benzoyl-benzenediazonium fiuoroborate prepared from 1 mole ofaminobenzophenone as in Example 23. The mixture was stirred overnight. Aprecipitate which formed was separated by filtration. The precipitatewas washed with cold water and extracted with about 1 liter of boil ingether. The ether layer was dried and filtered. To this solution (ca. 1liter), about 2 liters of petroleum ether was added. The mixture wascooled, the supernatant solution decanted and the residual insoluble oildiscarded. The decanted solution deposited crystals which were filteredoft (M.P. 80-91"). The so-filtered solution was concentrated and theresidual oil recrystallized from ethanol to give crystals, M.P. 7378.The crystals of M.P. 8091 and of MP. 7378 were combined. Aftercrystallization of the combination from an ether and petroleum ethermixture and then from dilute alcohol, slightly yellow crystals of2-thiocyano benzophenone were obtained, melting at 8282.5.

EXAMPLE 25 A solution of 5.5 g. (0.02 mole) of 2,3-dihydro-5-phenyl-1,4-benzothiazepine in 60 ml. of 3 N hydrochloric acid wasrefluxed for 21 hours. The reaction mixture was concentrated in vacuo todryness and the residue crystallized from a mixture of isopropanol andether. The crude product was purified by crystallization from the samesolvent mixture and formed colorless prisms of 2-(2-aminoethylthio)benzophenone hydrochloride melting at 152153.

EXAMPLE 26 To a refluxing, stirred solution of 4.7 g. 0.02 mole) of2,3-dihydro-5-phenyl-1,4-benzothiazepine in 100 ml. of methylenechloride was added Over a period of minutes, a solution of 1.6 ml.(0.021 mole) of sulfuryl chloride in ml. of methylene chloride. Thereaction mixture was refluxed for 1 hr. and the formed crystallineprecipitate was separated by filtration. The crystals were dissolved ina mixture of methylene chloride and ice cold dilute potassium hydroxide.The organic layer was separated, dried, and concentrated in vacuo todryness. The residue was crystallized from a mixture of ether andpetroleum ether to give prisms. Recrystallization from the same solventmixture gave colorless prisms of 2- chloro-2,3-dihydro-5-phenyl-1,4benzothiazepine melting at 9394.

EXAMPLE 27 To a stirred solution of 4.7 g. (0.02 mole) of2,3-dihydro-S-phenyl-1,4-benzothiazepine in 100 ml. of methanol cooledin an ice bath, 4.2 g. (0.02 mole) of sodium metaperiodate dissolved in40 ml. of water was added. The reaction mixture was stirred for 1 hourat 30 and 4 hours at room temperature. The resultant mixture wasfiltered. The filtrate was concentrated in vacuo to a small volume. Theconcentrate was extracted with methylene chloride and the organic layerwas separated, dried and concen trated in vacuo to dryness. The residuethus obtained was dissolved in ether and yielded crystalline2,3-dihydro-5- phenyl-l,4-benzothiazepine l-oxide. Recrystallization of16 the product from ether gave colorless prisms melting at 158160.

EXAMPLE 28 A solution of 12 g. (0.05 mole) of 2,3-dihydro-5-phenyl-l,4-benzothiazepine in a mixture of 130 ml. of acetic acid and 20ml. of 30% hydrogen peroxide was left at room temperature, exposed todaylight, for 17 days. The reaction mixture was diluted with water and4,5- epoxy 2,3,4,5 tetrahydro 5 phenyl 1,4 benzothiazepine 1,1-dioxidewhich precipitated was separated by filtration. The product was purifiedby crystallization from a mixture of methylene chloride and ether andformed colorless prisms melting at 169l70.

EXAMPLE 29' A solution of 2 g. of 4,5-epoxy-2,3,4,5-tetrahydro-5-phenyl-l,4benzothiazepine 1,1-dioxide in 60 ml. of xylene was refluxedfor /2 hr. and then cooled. The crystalline reaction product wasseparated by filtration. Recrystallization from mixture of methylenechloride and ether gave colorless needles of2,3-dihydro-5-phenyl-1,4-benzothiazepine 1,1,4-trioxide melting at 2389.

EXAMPLE 30 A solution of 23.9 g. (0.1 mole) of 2,3-dihydro-5-phenyl-l,4-benzothiazepine in 200 ml. of dry tetrahydrofuran was addedslowly at room temperature to a stirred suspension of 8 g. (0.2 mole) oflithium aluminum hydride in 600 ml. of tetrahydrofuran. The reactionmixture was refluxed for 2 hrs. and then cooled in an ice bath. Oneliter of wet ether was added slowly and the mixture filtered through ahyflo-bed. The filtrate was dried, concentrated in vacuo to dryness andthe residue dissolved in ether. On standing, crystalline2,3,4,S-tetrahydro-S-phenyl- 1,4-benzothiazepine was obtained.Recrystallization from ether gave colorless needles of the productmelting at 89-90.

EXAMPLE 31 To a stirred solution of 4.8 g. (0.020 mole) of 2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine in ml. of methanol cooled in anice bath, 4.2 g. (0.020 mole) of sodium meta-periodate dissolved in 40ml. of water was added. The reaction mixture was stirred for 4 hrs. atroom temperature. The resultant mixture was filtered and the filtrateconcentrated in vacuo to a small volume. The concentrate was extractedwith methylene chloride and the organic layer was separated, dried andconcentrated in vacuo to dryness. On addition of ether, crude2,3,4,5-tetrahydro-S-phenyl-1,4-benzothiazepine l-oxide crystallized.Recrystallization from a mixture of CH Cl and ether gave colorlessneedles of the product melting at 147-148".

EXAMPLE 32 To a stirred solution of 9.5 g. (0.04 mole) of 2,3,4,5-tetrahydro-S-phenyl-l,4-benzothiazepine in 50ml. of chlorobenzene, therewas added a solution of 12.2 g. (0.1 mole) of diethylaminoethyl chloride1 in 75 m1. of chlorobenzene. The mixture was refluxed for 18 hrs. andthen cooled. Crude 4-(Z-diethylaminoethyl)-2,3,4,5-tetarhydr0-S-phenyl-1,4-benzothiazepine hydrochloride crystallized out.Recrystallization from a mixture of methylene chloride and ether gavethe product as colorless needles melting at 193-194.

A solution of 1 g. of 4-(dimethylaminoethyl)-2,3,4,5-tetrahydro-S-phenyl-l,4-benzothiazepine hydrochloride in water wasfiltered by gravity, made basic with NaOl-I, and extracted with ether.The ether extract was dried over The solution of diethylaminoethylchloride was prepared as follows: To a. stirred suspension of 35 g. ofcrude diethylamiuoethyl chloride hydrochloride in 100 m1. ofchlorohenzene at -5 was added a solution of 9 g. of sodium hydroxide in20 ml. of Water. Stirring was continued for 30 minutes at 0. The organicsolution which contained diethylarninoethyl chloride was decanted fromthe slurry and dried over sodium sulfate for 6 hrs. An aliquotcontaining 0.1 mole thereof was taken for use above.

sodium sulfate and concentrated in vacuo to yield an almost colorlessoil of4-(2-diethylaminoethyl)-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine.The NMR spectrum was consistent with the structure of the compound andshowed the protons of the two equivalent ethyl groups (attached tonitrogen) a 7.501 and 9.021, the protons of three additional methylenegroups (adjacent to nitrogens) at 7.l7.501, the protons of the methylenegroup attached to sulfur at 6.65, one CH-proton at 4.227, and 9 aromaticprotons at 2.33.2r.

EXAMPLE 33 To a solution of 31 g. of 7-chloro-2,3,4,5-tetrahydro-S-phenyl-l,4-benzotihazepine hydrochloride in 120 ml. of alcohol, therewas added 100 ml. of 3 N sodium hydroxide. The liberated base wasextracted with ether. The ether solution was dried and concentrated invacuo. To the oily residue, 75 ml. of chlorobenzene and a solution of 45g. of diethylaminoethyl chloride (prepared from 60 g. of thehydrochloride as in Example 32) in 100 ml. of chlorobenzene was added.The mixture was stirred, refluxed for 20 hrs. and cooled. Crude7-chloro-4-(2-diethylaminoethyl)-2,3,4,5-tetrahydro--phenyl 1,4benzothiazepine hydrochloride precipitated, was filtered off andpurified by recrystallization from acetone. It formed colorless needlesmelting at 195-196".

Example 34 To 60 ml. of concentrated sulfuric acid, cooled to 6.9 g.(0.1 mole) of sodium nitrite was added slowly with stirring. The mixturewas then heated to about 80 until a clear solution formed. After coolingto 45, 26.5 g. (0.1 mole) of Z-amino-5-trifluoromethylbenzophenone wasadded in portions keeping the temperature between 45-50". After stirringfor 1 hr., the solution was poured slowly into 400 ml. of ice-water.After filtration, a solution of 20 g. of sodium fluoroborate in 80 ml.of water was added to the filtrate, 2 benzoyl-4-trifluoromethyl-benzenediazonium fluoroborate precipitated. It was separated by filtration andthen washed with a small amount of water. The so-washed precipitate wasadded over a period of 5 minutes to a vigorously stirred solution of 24g. (0.15 mole) of recrystalized potassium ethyl xanthate in 200 ml. ofwater heated to 70. After the addition was completed, the mixture wasstirred for 5 min., cooled and extracted with ether. The ether extractwas dried over sodium sulfate, filtered and the filtrate concentrated invacuo to dryness. T heoily crude residue containing ethyl xanthic acid2abenzoyl-4-trifiuoromethylphenyl ester was obtained. A solution of 20g. of potassium hydroxide in a mixture of 60 ml. of water and 60 ml. ofethanol was added to the oily crude residue. The reaction mixture wasthen stirred and refluxed for 10 min., while 3.5 g. of zinc dust wascarefully introduced. 150 ml. of water was then added, and the mixturewas filtered over a filter aid, and washed with 50 ml. of water. Thefiltrate containing 2-mercapto-5-trifluoromethylbenzophenone was cooledto room temperature, and a solution of 20 g. of bromoethylaminehydrobromide in 35 ml. of water was added. After stirring for 30 min.,the reaction mixture was extracted with methylene chloride and theorganic layer dried over sodium sulfate and filtered. The filtrate wasacidified with methanolic hydrochloric acid and concentrated in vacuo.To the residue, consisting of2-2-aminoethylthio)-5-trifluoromethylbenzophenone and2,3-dihydro-5-phenyl-7- trifluoromethyl-1,4-benzothiazepine, 100 ml. ofpyridine was added. The solution was refluxed for 2 hrs. and thenconcentrated in vacuo. The residue was then dissolved in a mixture ofether and water. The organic layer was separated, dried and concentratedin vacuo to dryness. The residue was dissolved in an excess ofmethanolic hydrogen chloride and concentrated in vacuo to dryness. Theso-obtained residue was crystallized from a mixture of Techn1cn1 gradeethyl xanthate was recrystallized from a five-fold amount of boilingethanol.

methylene chloride, ether and petroleum ether yielding crude2,3-dihydro-5 phenyl-7-trifiuoromethyl 1,4-benzothiazepinehydrochloride. The product was recrystallized from isopropanol and gaveyellow prisms of the product melting at 231-232. The base, namely,2,3-dihydro-5- phenyl 7 trifluoromethyl 1,4 benzothiazepine, wasliberated from the hydrochloride in an ice cold mixture of ether anddilute sodium hydroxide. The organic layer was dried and concentrated invacuo. to dryness. The residue was recrystallized from petroleum etherand gave colorless prisms of the free base melting at 9l.

Example 35 To a solution of 2.2 g. of Z-meroaptoethylamine hydrochloridein ml. of pyridine was added 1 g. of 53% sodium hydride in 5.6 g. of2-chloro-5-trifluoromethylbenzophenone. The reaction mixture was heatedon the steam bath for 3 hrs. and then concentrated in vacuo to dryness.Cold dilute hydrochloric acid and ether was added to the residue and5-trifluoromethyl-2-(Z-aminoethylthio) benzophenone hydrochloride whichprecipitated was separated by filtration. Recrystallization of theproduce from isopropanol gave colorles needels melting at 178179.

This product could be cyclized to 2,3-dihydro-5-phenyl-7-trifluoromethyl-1,4-benzothiazepine hydrochloride by treatment withboiling pyridine.

Example 36 7.5 g. of 6'-amino-3,4-dimethoxyacetophenone was added to 70ml. of dilute hydrochloric acid (1:1). The resultant mixture was heatedat 50 until complete solution, then placed in an ice-bath, and stirreduntil the inside temperature had dropped *below +5". To the finesuspension, thus obtained, there was added dropwise a solution of 2.9 g.of sodium nitrite in 5 ml. of water at such a rate as to maintain thetemperature at 0 to +5. After the addition was completed, the mixturewas stirred in the ice-bath for 1 /2 hours. A filtered solution of 7.7g. of sodium fluoroborate in 30 ml. of water was added and the mixturestirred for 30 minutes. 2-acetyl-4,5-dimethoxy benzene diazoniumfluoroborate which precipitated was collected by filtration and washedwith water.

8.5 grams of the precipitated diazonium fluoroborate while still damp,was added in small portions to a solution of 8 g. of potassium ethylxanthate in 50 ml. of water. During the addition, the temperature wasmaintined at 70-7 5 After the addition was completed, heating wascontinued for 15 minutes. The cooled mixture was extracted with ether.The ether extract was washed with 5% sodium hydroxide solution, thenwith water, and dried over sodium sulfate. The oily residue, obtainedafter removal of the solvent, was taken up in a small amount of ether.The ethyl xanthic acid-2-acetyl-4,5-dimethoxyphenyl ester of M.P. 9293precipitated and was isolated by filtration. Recrystallization fromdilute ethanol raised the M.P. of the product to 9495.

Example 37 7.5 g. of 6'amino 3',4 dimethoxyacetophenone was dissolved in70 ml. of dilute hydrochloric acid (1:8) at 40. To the coled solutionwas added dropwise a solution of 2.9 g. of sodium nitrite in 10 ml. ofwater while maintaining the temperature of the reaction mixture at 0 to+5 After the addition was completed, the so-formed diazonium solutionwas stirred for 1 hour in the cooling bath and was then added in smallportions to a solution of 8 g. of potassium ethyl xanthate in 10 ml. ofwater. During the addition, the temperature was maintained at 70-75.After about three quarters of the diazonium chloride solution has beenadded, 1 g. of sodium carbonate was added to the xanthate solution tokeep the reaction mixture alkaline. After the addition was completed,the mixture was heated for 30 minutes, cooled and extracted with ether.The ether extract was washed with 5% sodium 19 hydroxide solution, thenwith water, and dried over sodium sulfate. After removal of the solvent,the viscous residue was dissolved in a minimum of ether. Crystals ofethyl xanthic acid 2 acetyl-4,S-dimethoxyphenyl ester which appeared,were isolated by filtration and were found to have a melting point of9193.

EXAMPLE 38 To a solution of 37.5 g. of copper sulfate in 150 ml. ofwater (90) there was added a solution of 34.5 g. of potassiumthiocyanate in 75 ml. of water. The precipitated copper thiocyanate wasfiltered off, washed with water, and suspended in 150 ml. of watercontaining 90 g. of potassium thiocyanate. To the stirred suspension,there was added dropwise the diazonium chloride solution prepared from30 g. of 6-amino-3,4'-dimethoxyacetophenone as in Example 37. During theaddition the temperature of the reaction mixture was maintained at70-75". After the addition was completed, the mixture was stirred andheated for 15 minutes. The precipitate which formed was filtered off,washed with water and dried in vacuo at 50. The dried solids wereextracted three times with 200 ml. of ethanol. The combined extracts, oncooling, deposited 3,4 dimethoxy-6-thiocyanatoacetophenone incrystalline form. After recrystallization from acetonitrilewater, the3,4 dimethoxy 6 thiocyanatoacetophenone melted at 144146.

EXAMPLE 39 3,4dimethoxy 6 thiocyanatoacetophenone was prepared as inExample 38, but instead of using the diazonium chloride solution, thecorresponding fiuroroborate salt was used in the reaction. It was addedto the copper thiocyanate suspension at 70 to 75 and the reaction wasworked up as described in Example 38. 60 g. of6'-amino-3,4-dimethoxyacetophenone was employed as the startingmaterial.

EXAMPLE 40 To a suspension of 18 g. of3,4-dimethoxy-6-thiocyanatoacetophenone and 14 g. of sodium hydrosulfitein 220 ml. of ethanol, there was added 54 ml. of 40% sodium solution.The resultant mixture was refluxed for 30 minutes in a nitrogenatmosphere. To the cooled mixture, there was added a solution of 20 g.of 2-bromoethylamine hydrobromide in 40 ml. of water. The mixture wasstirred at room temperature for one hour and then heated on the steambath for an additional hour. The mixture was then filtered. The filtratewas diluted with 1 liter of water and extracted with methylene chloride.The extract was dried over sodium sulfate, filtered, acidified withethanolic hydrochloric acid, and evaporated to dryness in vacuo. Theresidue was dissolved in hot ethanol, filtered and cooled. Addition ofexcess ether precipitated 2,3 dihydro 7,8 di|methoxy--methyl1,4-benzothiazepine hydrochloride in the form of yellow crystals. Afterrecrystallization from ethanol-ether, the compound was found to have amelting point of 20 1- 203 (dec.).

The free base was obtained by dissolving the2,3-dihydro-7,8-dimethoxy-5-methyl-1,4-benzothiazepine hydrochloride inWater, making the solution alkaline, and extracting with ether. Thedried ether extract was evaporated to dryness, and the residuerecrystallized from heptane giving the base of melting point l-103.

EXAMPLE 41 7 g. of ethylxanthic acid 2-acetyl-4,S-dimethoxyphenyl esterwas dissolved in ml. of 30% ethanolic potassium hydroxide and refluxedfor 1 hour, under nitrogen. To the cooled solution, there was added 6.2g. of 2-bromoethylamine hydrobromide. The resultant mixture was stirredfor 1 hour at room temperature, filtered and taken to dryness. To theresidue was added chloroform and water. The chloroform layer wasseparated, dried and evaporated to dryness. The residue was dissolved inml. of pyridine and refluxed for 2 hours, after which time the resultantsolution was evaporated to dryness. The residue was taken up in waterand chloroform and then the organic layer was separated, dried and takento dryness. The residue was dissolved in a minimum of ethanol andacidified with hydrochloric acid. 2,3-dihydro- 7 ,8-dimethoxy-5-methyl1,4 benzothiazepine hydrochloride which precipitated was separated byfiltration. After recrystallization from ethanol-ether, the compound wasfound to have a melting point of 200-201" (dec.).

EXAMPLE 42.

1 g. of 2,3-dihydro-7,8-dimethoxy-5-methyl-1.,4-benzothiazepinehydrochloride was refluxed in 20 ml. of 3 N hydrochloric acid for 18hours. The hot solution was treated with charcoal, filtered and chilled.6 -(2-aminoethylmercapto) 3',4-dirnethoxyacetophenone hydrochlorideprecipitated as crystals and was isolated by filtration. Uponrecrystallization from ethanol, the product was found to have a meltingpoint of 177-178.

EXAMPLE 43 11.8 g. of 2,3 dihydro 7,8 dimethoxy-S-methyl-IA-benzothiazepine hydrochloride was dissolved in 200 ml. of water. 44 ml.of l N sodium hydroxide was added and the mixture homogenized by theaddition of 100* ml. of ethanol. To the alkaline solution, there wasadded a solution of 9.5 g. of sodium borohydride in ml. of water. Theresultant mixture was allowed to stand at room temperature for 18 hours.The solution was acidified, diluted with 500 ml. of Water, made alkalineagain and extracted with methylene chloride. The extract Was washed withwater, dried over magnesium sulfate and filtered. The filtrate wasacidified with hydrochloric acid and evaporated to dryness. 7,8dimethoxy 5 methyl- 2,3,4,5-tetrahydro-1,4-benzothiazepine hydrochloridewas obtained as a white solid which melted at 259-261".Recrystallization from ethanol-ether raised the melting point to26'1-263.

The free base was prepared by dissolving the last-mentionedhydrochloride in water, making the solution alkaline and extracting withether. The dried ether extract was evaporated to dryness and the residuewas recrystallized from methanol-water giving7,8-dimethoxy-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine as whitecrystals, M.P. 5759.

EXAMPLE 44 2.7 g. of 7,8-dimethoxy-5-methyl-2,3,4,S-tetrahydro-l,4-benzothiazepine hydrochloride was dissolved in 25 ml. of glacial aceticacid. 4.4 g. of 30% hydrogen peroxide was added, and the mixture allowedto stand at room temperature for 2 weeks. After removal of the solvent,the residue was treated with hot methylenechloride and the solidsisolated by filtration. After recrystallization from methanol ether,7,S-dimethoxy-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide hydrochloride was obtained of M.P. 252254 (dec.).

The free base was prepared by dissolving the lastmentioned hydrochloridein water, making the solution alkaline and extracting with ether. Thedried ether extract was evaporated to dryness and the residue was addedto benzene and crystallized from /2 mole of benzene, yielding crystalsof melting point 151-153 C.

After drying for 24 hours in vacuo at 110,7,8-dimethoxy-S-methyl-Z,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide was obtained in pure form, M.P. 151-153.

EXAMPLE 45 To a solution of 10 g. of copper sulfate in 50 ml. of waterthere was added a solution of 5 g. of potassium thiocyanate in 20 ml. ofwater. The precipitated copper thiocyanate was filtered off, washed withWater and suspended in ml. of water containing 25 g. of potassiumthiocyanate. 12.6 g. of 6-amino-3,4-dimethoxyphenyl phenethyl ketone wassuspended in 300 ml. of 1 N hydrochloric acid and the suspension heatedon the steam bath for 15 minutes. After cooling, a solution of 3.5 g. ofsodium nitrite in 20 ml. of water was added dropwise with stirring at atemperature of to Upon completion of such addition, the suspension wasstirred in a cooling bath for 1 hour and yielded 4,5-dimethoxy-2-(3-phenylpropionyl)-benzene diazonium chloride. This suspension wascarefully added to the copper thiocyanate suspension while maintainingthe temperature of the reaction mixture at 70-75" during such addition.After the addition was completed, the mixture was stirred and heated for20 minutes. The precipitate which formed was filtered off, washed withwater and dried in vacuo at 50. The dried solids were extractedrepeatedly with acetonitrile. The combined extracts, on chilling,deposited crystals of 3,4-dimethoxy-6-thiocyanatophenyl phenethylketone. After recrystallization from acetonitrile-water, the productmelted at 145146.

EXAMPLE 46 To a solution of 16 g. of copper sulfate in 65 m1. of water(90") there was added a solution of 14.5 g. of potassium thiocyanate in35 ml. of water. Copper thiocyanate precipitated. The precipitate wasfiltered off, washed with water and suspended in 65 ml. of watercontaining 25 g. of potassium thiocyanate. To the stirred suspension,there was added dropwise a 4-bromo-2-(2-picolynoyl)benzene diazoniumchloride solution prepared by dissolving 14 g. of 6-amino-3-bromophenyl2-pyridyl ketone in 130 ml. of dilute hydrochloric acid (1:8), coolingthe so-formed solution, adding the same dropwise to a solution of 4 g.of sodium nitrite in 15 ml. of water at a temperature range of 0+5 andafter completion of such addition, stirring for 1 hour in the coolingbath. During the addition of the diazonium chloride solution to thestirred suspension, the temperature of the reaction mixture wasmaintained at 70-75. After the addition was complete, 8 g. of sodiumbicarbonate was added and the mixture cooled. The precipitate whichformed was filtered off, washed with water and dried in vacuo at 50. Thedried solids were extracted repeatedly with hot ethanol. The combinedextracts on cooling yielded crystals of 3-bromo-6-thiocyanatophenyl2-pyridyl ketone. After recrystallization from ethanol, thelast-mentioned product melted at 159-161.

EXAMPLE 47 To a suspension of 6.3 g. of 3-borom-6-thiocyanatophenyl2-pyridyl ketone and 3.5 g. of sodium hydrosulfite in 60 ml. of ethanol,there was added 15 ml. of 40% sodium hydroxide solution. The resultantmixture refluxed for 30 minutes under nitrogen. To the cooled mixturewas added a solution of 4.4 g. of 2-bromoethylamine hydrobromide in 10ml. of water. The mixture was stirred for one hour at room temperatureand heated for one hour on the steam bath. The mixture was diluted with200 ml. of water and extracted with methylene chloride. The extract wastreated with charcoal, acidified with ethanolic hydrochloric acid, andtaken to dryness. To the residue there was added a minimum of ethanol.Crystals of 7- bromo-2,3-dihydro-5-(Z-pyridyl)-1,4-benzothiazepinehydrochloride which formed were filtered 0E. The mother liquors, onstanding for 24 hours, yielded additional crys tals of thelast-mentioned product. The crystals were combined, and recrystallizedfrom ethanol-ether to give yellow crystals of the product melting at205-210 (dec.)

EXAMPLE 48 To a suspension of 2.1 g. of3-bromo-6-thiocyanatophenyl-Z-pyridyl ketone and 1.1 g. of sodiumhydrosulfite in 20 ml. of ethanol, there was added 5 ml. of 40% sodiumhydroxide solution. The mixture was heated for 30 minutes undernitrogen. To the cooled mixture, there was added a solution of 1.5 g. of2-bromoethylamine hydrobromide in 3 ml. of water. After stirring for onehour at room temperature, 75 ml. of water was added. The mixture wasextracted with methylene chloride. The extract was treated Withcharcoal, dried over magnesium sulfate, and concentrated in vacuo to asmall volume. Addition of a small amount of ethanol inducedcrystallization. 7- bromo-2,3-dihydro-5-(2-pyridyl)-1,4 benzothiazepinein the form of crystals was isolated by filtration. From the motherliquors an additional amount of the product in crystalline form wasobtained. The crystals were combined and after recrystallization fromisopropanol, the product melted at l66168.

EXAMPLE 49 To a solution of 2.4 g. of 7,8-dimethoxy-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine in 35 ml. of chlorobenzene, there wasadded 3.4 g. of 2-diethylaminoethyl chloride. The resultant mixture wasrefluxed for 16 hours. The cooled solution was filtered from someinsolubles and chilled. Upon chilling, white crystals of4-(2-diethylaminoethyl)-7,8-dimethoxy 5methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine hydrochloride wereisolated by filtration. Upon recrystallization from ethanol-ether, theproduct was found to have a melting point of 172-174.

EXAMPLE 50 A solution of 12.2 g. (0.04 mole) of 2,3-dihydro-7-trifiuoromethyl-S-phenyl-1,4-benzothiazepine in 200 -ml. of drytetrahydrofuran was added slowly at room temperature to a stirredsuspension of 3.0 g. (0.08 mole) of lithium aluminum hydride in 200 ml.of tetrahydrofuran. The reaction mixture was refluxed for 2 hr. and thencooled in an ice bath. One liter of wet ether was added slowly and thenthe mixture was filtered through a hyfiobed. The filtrate was dried andconcentrated in vacuo to dyness. The residue was dissolved inisopropanol and acidified with a solution of hydrogen chloride inisopropanol. On standing, crystalline2,3,4,5-tetrahydro-7-trifluoromethyl-S-phenyl-l,4-benzothiazepinehydrochloride was obtained. Recrystallization of the product fromisopropanol gave colorless prisms melting at 25 5-25 7.

EXAMPLE 5 1 An ampul containing 7- chloro-2,3-dihydro-5-phenyl-l,4-benzothiazepine hydrochloride suitable for parenteral use is preparedas follows:

mg. of a parenteral grade of 7-chloro-2,3-dihydro-S-phenyl-1,4-benzothiazepine hydrochloride, fiber free, is filled into a5 cc. ampul using a Diehl Mater electric filler. The ampuls are sealedand sterilized at 255 F. for 2 hours.

Immediately before use, the powder is solubilized with 5 cc. of waterfor inspection, U.S.P. and is thus placed in a form suitable forparenteral use.

EXAMPLE 52 A tablet dosage form containing 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine hydrochloride as the active component wasprepared. It had the following composition:

Ingredient: Per tablet, mg.

7 chloro 2,3 dihydro-S-phenyl-1,4-benzothiazepine hydrochloride 5.0Lactose 113.5 Corn starch 70.5 Pregelatinized corn starch 8.0 Calciumstearate 3.0

Total weight 200.0

The procedure for preparing the tablet dosage form is as follows:

In a suitable size mixer, mix the active component,

lactose, corn starch and regelatinized corn starch. Pass the mix througha Fitzpatrick Comminuting Machine fitted with #1A screen and with knivesforward. Return to the said mixer and moisten with water to a thickpaste. Pass the moist mass through a #12 screen and dry the moist 23granules on paper lined trays at 110 F. Return the dried granules to themixer, add the calcium stearate and mix well. Compress the granules at atablet weight of 200 mg., using standard concave punches having adiameter of PAS!!- EXAMPLE 53 A capsule dosage formulation containing7-chloro-2,3- dihydro-S-phenyl-1,4-benzothiazepine hydrochloride as theactive component was prepared. It had the following composition:

Ingredient: Per capsule, mg.

7 chloro-2,3-dihydro--phenyl-l,4-benzothiaze- I pine hydrochloride 1OLactose 158 Corn starch 37 Talc 5 Total weight 210 The procedure forpreparing the capsule dosage formulation was as follows:

Mix the active component with lactose and corn starch in a suitablemixer. Further blend the mixture by passing it through a FitzpatrickComminuting Machine with a No. 1A screen and with knives forward. Returnthe blended powder to the mixer, add the tale and blend thoroughly. Fillinto No. 4 hard shell gelatin capsules on a Parke Davis or similar typecapsulating machine.

EXAMPLE 54 A suppository dosage formulation containing 7-chloro- 2,3dihydro-S-phenyl-1,4-benzothiazepine hydrochloride as the activeingredient was prepared. It had the following composition:

Ingredient: Per 1.3-gm. suppository, gm.

7 chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine hydrochloride 0.010Wecobee M 1.245 Carnauba wax 0.045

1A synthetic cocoa butter base manufactured by the E. F. Drew Company,522 5th Ave., New York, NY.

The procedure for preparing the suppository dosage formulation was asfollows:

Melt the Wecobee M and the carnauba wax in a suitable size glass linedor stainless steel container, mix well and cool the mixture to 45 C. Addthe drug which has been reduced to a fine powder with no lumps and stiruntil completely and uniformly dispersed. Pour the mixture intosuppository molds suitable for providing suppositories having anindividual weight of 1.3 gms. Cool and remove from molds.

We claim:

1. A process which comprises reacting a compound of the formula whereinX is selected from the group consisting of an anion of a strong mineralacid and a B'F -radical; D is selected from the group consisting oflower alkyl and R and R are selected from the group consisting ofhydrogen, halogen, nitro, lower alkyl, lower alkoxy, trifiuoromethyl,lower alkyl thio, lower alkyl sulfinyl and lower alkyl sulfonyl; and Ris selected from the group consisting of hydrogen, lower alkyl, halogenand trifiuoromethyl with a copper thiocyanate twhereby to prepare acompound having the formula of wherein R, R and D are as above,

hydrolyzing the compound of Formula 11 above to thereby prepare acompound having the formula of SH R1 l 1) III wherein R, R and D are asabove, and reacting the resulting product with a compound having theformula wherein R and R are selected from the group consisting ofhydrogen and lower alkyl.

2. A process as defined in claim 1 wherein R is hydrogen, R is halogenand is present at the 4 position of the starting diazonium-fluoroborateand D is phenyl.

3. A process as defined in claim 2 wherein the metal thiocyanateutilized is copper thiocyanate and the compound of Formula IV utilizedis bromoethylamine.

4. A compound as defined in claim 1 wherein in the diazonium startingmaterial utilized, R and R are hy drogen and D is phenyl.

5. A process as defined in claim 1 which utilizes as the diazoniumstarting material, a compound of the formu a 6. A process as defined inclaim 1 which utilizes as the diazonium starting material a compound ofthe formula C1130 Nz-X CHaO (3 0 References Cited UNITED STATES PATENTS3,155,649 11/1964 Krapcho et al 260239.3

ALAN L. ROTMAN, Primary Examiner US. Cl. X. R.

Poqobo UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3.530.139 Dated Sept mber 2? 1970 Inventor) Reeder and SternbaQh It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

r Column 24, line 64 Claim 6 '1 CH 0 N Y V\\ CH3O --:c|:= o

should be CH 0 11 x h c11 0 W\ I CH Signed and sealed this 22nd day ofDecember 1970.

( Meat:

Edward M. Fletcher, In I "II-LIAM E- BGHUYLER, m.

l Officer Commissioner or Pate'nta

